Prostate cancer is the most common cancer in men and is the second leading cause of cancer deaths in men in the United States. Despite its enormous impact on male health, the molecular mechanisms underlying the pathogenesis of prostate cancer, especially issues related to metastasis and resistance to androgen ablation therapy, remain relatively unknown in comparison with other common cancers. The PTEN tumor suppressor gene is deleted in 30% of primary prostate cancers and 63% of prostate metastatic lesions, placing PTEN loss among the most common genetic alterations in human prostate cancers. The long term objective of this application is to understand the molecular mechanisms underlying prostate tumor initiation, progression, metastasis, and hormone resistance, and to identify new targets for drug development as well as new biomarkers for monitoring treatment, using our genetically defined murine Pten conditional knock-out model. Aim I will focus on characterization of the course of the disease in this model and on the location and the cell types associated with prostate cancer metastasis. "Reporter mice" have been generated for this purpose for in vivo, non-invasive imaging and for tracking specific cell types during tumor progression and metastasis. We will directly test the hypothesis that prostate cancer may arise from dysregulated stem/progenitor cells. Since the murine Pten prostate cancer model is the only model currently available in which the primary tumorigenic lesion is not regulated by androgen, Aim 2 will dissect hormone resistant mechanisms and identify the cellular origin of hormone refractory prostate cancer. Finally, tumor tissues and cell lines will be used for genome-wide microarray analyses and comparative genome hybridization analyses. This dataset will be compared with similar datasets from human prostate cancers to identify key molecular events in prostate cancer progression, metastasis, and hormone resistance. Candidate genes will be further evaluated biochemically and genetically for their contributions to prostate cancer development. Although focused on prostate cancer, the studies outlined here and the mechanisms elucidated in this proposal will be broadly relevant to cancers associated with PTEN loss in general, since PTEN is expressed in all cell types in our body and PTEN mutations are observed in many human cancers.